Abstract

Since the original description of CSCs in solid tumors in 2003, emerging evidence suggests the presence of multiple breast CSC states (CD44+CD24-EpCAM+, ALDH+) that might be responsible for distinct processes in breast cancer progression such as metastasis, invasion, and proliferation. It has been hypothesized that CSCs contribute to the cellular heterogeneity within cancer, the metastatic spread, and eventual recurrence. As chemotherapy and radiation are relatively ineffective at targeting CSCs, therapeutic agents that target the relatively rare CSC population are highly needed.

To this end, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogenic protein whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including breast, ovarian, and endometrial tumors. Clinical data also revealed higher levels of EMP2 in metastatic lesions compared to primary tumors and high expression in triple negative breast cancer. In this study, we show new evidence that EMP2 is highly expressed in CSCs and regulates their proposed functions, namely mammosphere formation and invasion. Moreover, in vivo modulation of EMP2 expression in both triple negative and HER2 positive tumors show that EMP2 promotes ALDH1 expression as well as increases tumor load.

We have recently developed a novel IgG1 monoclonal antibody to EMP2 termed PG-101, and we have shown that this therapy reduces primary. We now have evidence that PG-101 treatment in the primary tumor is sufficient to reduce secondary tumor formation in triple negative breast cancer cells on the order of 1:20,000 compared to the control treated mice. To extend on the benefits of PG-101, we have combined it with docetaxel in an effort to mimic the clinical setting given that the vast majority of patients treated in the neoadjuvant setting have a taxane as part of the regimen. Data using triple negative xenografts show that PG-101 in combination with docetaxel can cure up to 80% of animals treated. This effect is lasting as these mice have shown no rebound in tumor load more than 2 months following the last treatment. Collectively, these results show that PG-101 therapy has the potential to revolutionize the outcomes for women with breast cancer.